Blocking serotonin receptors has been shown to result in a number of beneficial pharmacological effects, including reduction in disease states such as hypertension, depression, anxiety, and the like; see U.S. Pat. No. 5,141,944. Nelson et al., Psychopharmacology and Biochemistry of Neurotransmitter Receptors, eds. H. I. Yamamura et al., Elsevier/North Holland Inc., p 325, have confirmed that there are multiple serotonin recognition sites. The general class of serotonin receptors are referred to as the 5-HT receptors. Specific 5-HT receptor sites include 5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2C, 5-HT.sub.3, and 5-HT.sub.4 sites. Each of these receptors mediates certain physiological effects. See Leonard, B. E., International Clinical Psychopharmacology, 7:13-21 (1992).
This invention provides new compounds and a method for using such compounds which are active at the 5-HT.sub.2B receptor to treat or prevent 5-HT.sub.2B related conditions. Further, this invention provides a method for selectively blocking the 5-HT.sub.2B receptor. Additionally, this invention provides a method for blocking human 5-HT.sub.2B receptors.
This invention provides a group of compounds which are 5HT.sub.2B receptor antagonists. Applicants have discovered that such compounds are potent competitive inhibitors of serotonin-induced contraction of the colon. Thus, this invention provides compounds which can act to normalize gastrointestinal motility and be useful in the treatment of Functional Bowel Disorders.
Further, it has been discovered the 5-HT.sub.2B receptor is localized in the rat lung, stomach fundus, uterus, bladder, and colon. Interesting areas of 5-HT.sub.2B receptor localization in the human include but are not limited to the brain and blood vessels. Thus, conditions which can be treated using a compound which modulates a 5-HT.sub.2B receptor includes, for example, psychosis, depression, anxiety disorders, uterine diseases such as endometriosis, fibrosis, and other abnormal uterine contractivity, panic attack, migraine, eating disorders, seasonal affective disorder, consumption disorders, cardiovascular conditions, such as thrombosis, hypertension, angina, vasospasm, and other vascular occlusive diseases, incontinence, bladder dysfunction, respiratory/airway disorders including asthma, and the like.
SUMMARY OF THE INVENTION
This invention provides a group of novel compounds with 5-HT.sub.2B receptor activity. Additionally, the present compounds are useful tools to characterize the effects of the 5-HT.sub.2B receptor and to develop therapeutic agents based on 5-HT.sub.2B receptor modulation.
The present invention provides compounds of the Formula I ##STR1##
wherein Q is selected from the group consisting of hydrogen, R.sub.34, and (CHR.sub.2)R.sub.4 ;
R3.sub.4 is spiro-bicyclic, substituted spiro-bicyclic, bicyclic or substituted bicyclic; PA1 R.sub.1 is hydrogen or C.sub.1 -C.sub.3 alkyl; PA1 R.sub.2 is hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 R.sub.3 is hydrogen or C.sub.1 -C.sub.3 alkyl; PA1 R.sub.4 is C.sub.5 -C.sub.8 cycloalkyl, substituted C.sub.5 -C.sub.8 cycloalkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, bicyclic or substituted bicyclic; PA1 m is 1 or 2; PA1 R.sub.5 is independently hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sub.5 ' is C.sub.1 -C.sub.4 alkyl; PA1 R.sub.8 is independently selected from the group consisting of an R.sub.6 group, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, C.sub.7 -C.sub.16 arylalkyl; or PA1 R.sub.6 and R.sub.7 together with the carbon atoms of group A form a 5- to 8-member carbon ring; PA1 R.sup.30 and R.sup.31 join to form a 3 to 8 member carbon ring; or PA1 R.sup.30 and R.sup.31 are independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.2 -C.sub.6 alkenyl; or PA1 a pharmaceutically acceptable salt or solvate thereof. PA1 m is 1 or 2; PA1 R.sub.8 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.2 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5., (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, OR.sub.5, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl, substituted C.sub.5 -C.sub.8 cycloalkenyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, and C.sub.7 -C.sub.16 arylalkyl; PA1 R.sub.5 is independently hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sub.5 ' is C.sub.1 -C.sub.4 alkyl; PA1 R6 and R7 together with the carbon atoms of group A form a 5- to 8-member carbon ring; PA1 Rg and R.sub.10 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, C.sub.7 -C.sub.16 arylalkyl; PA1 R.sub.11 is selected from the group consisting of C.sub.1 -C.sub.4 alkyl, OR.sub.5 ', fluoro, bromo, iodo, and chloro; PA1 R.sup.30 and R.sup.31 join to form a 3 to 8 member carbon ring; or PA1 R.sup.30 and R.sup.31 are independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl and C.sub.2 -C.sub.6 alkenyl; or PA1 a pharmaceutically acceptable salt or solvate thereof. PA1 A) R.sub.1 is hydrogen; PA1 B) R.sub.2 is hydrogen or methyl; PA1 C) R.sub.3 is hydrogen or methyl; PA1 D) R.sub.4 is C.sub.5 -C.sub.8 cycloalkenyl or substituted C.sub.5 -C.sub.8 cycloalkenyl, wherein the substituents are selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, NO.sub.2, halo, halo(C.sub.1 -C.sub.6)alkyl, C.sub.2 -C.sub.6 alkenyl, COR.sub.5, (C.sub.1 -C.sub.6 alkyl).sub.m amino, --SR.sub.5, and OR.sub.5 ; PA1 E) A is a group of formula III; PA1 F) A is a group of formula IV wherein R.sub.6 and R.sub.7 are C.sub.1 -C.sub.6 alkyl or halo, and R.sub.8 is hydrogen, C.sub.1 -C.sub.5 alkyl, halo, C.sub.5 -C.sub.8 cycloalkyl, phenyl or substituted-phenyl; PA1 C) R.sub.2 is hydrogen; PA1 H) R.sub.3 is hydrogen; PA1 I) R.sub.4 is substituted C.sub.5 -C.sub.8 cycloalkenyl; wherein the substituents are selected from the group consisting of hydrogen, NO.sub.2, halo, (C.sub.1 -C.sub.6 alkyl).sub.m amino, and OR.sub.5 ; PA1 J) A is a group of formula IV wherein R.sub.6 is hydrogen, R.sub.7 and R.sub.8 are independently selected from the group consisting of halo and C.sub.1 -C.sub.4 alkyl. PA1 K) Q is (CHR.sub.2)R.sub.4 ; PA1 L) R.sup.30 and R.sup.31 join to form a 3 to 6 member carbon ring; PA1 M) R.sup.30 and R.sup.31 join to form a 3 to 5 member carbon ring; PA1 N) R.sup.30 and R.sup.31 are each methyl; PA1 O) R.sub.4 is naphthyl; PA1 P) R.sub.4 is an optionally substituted bicyclic hydrocarbon ring system having 7 to 12 carbon atoms and 0, 1, 2, or 5 double bonds; PA1 Q) R.sub.4 is a 6 to 10 carbon atom unsaturated bicyclic ring system; PA1 R) Q is bicyclic or substituted bicyclic; PA1 S) R.sub.34 is ##STR6## T) R.sub.34 is an optionally substituted bicyclic ring substituent; U) R.sub.9 and R.sub.10 are each hydrogen; PA1 V) Rg is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkyl-(C.sub.1 -C.sub.3)alkyl, C.sub.5 -C.sub.8 cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, C.sub.7 -C.sub.16 arylalkyl; PA1 W) R.sub.4 is aromatic; PA1 X) R.sub.34 is spiro-bicyclic or substituted spiro-bicyclic; PA1 Y) Q is hydrogen. PA1 A-C, E or F, I, L, N, P, R, and W. PA1 A, G-J, M, and Q. PA1 A-D, E or J, M, and O. PA1 A, G-J, M, and 0. PA1 A) R.sub.9 and R.sub.10 are each hydrogen; PA1 B) R.sub.11 is C.sub.1 -C.sub.3 alkyl; PA1 C) R.sub.11 is chloro, fluoro, or bromo; PA1 D) R.sub.11 is --OCH.sub.3 ; PA1 E) R.sup.30 and R.sup.31 join to form a 3 to 8 member carbon ring; PA1 F) R.sup.30 and R.sup.31 join to form a 3 to 6 member carbon ring; PA1 G) A compound having preferred compound characteristics described supra; PA1 H) A method for binding a 5HT.sub.2B receptor using one or more compounds of Formula I and/or II; PA1 I) A method of using one or more compounds of Formula I and/or II for treating a functional bowel disorder. PA1 I) A method of using one or more compounds of Formula I and/or II which are useful for modulatation of the 5HT.sub.2B receptor for treating a function bowel disorder. PA1 J) A method for using one or more compounds of Formula I and/or II for treating Irritable Bowel Syndrome. PA1 K) A pharmaceutical formulation comprising a compound of Formula I and/or II and one or more pharmaceutically acceptable excipients.
A is selected from the group consisting of ##STR2##
wherein
R.sub.6 and R7 are, independently, hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.1 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5 ', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, or OR.sub.5 ;
This invention provides compounds of Formula II ##STR3##
A is selected from the group consisting of ##STR4##
wherein
R.sub.6 and R.sub.7 are, independently, hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, halo, halo(C.sub.1 -C.sub.6)alkyl, halo(C.sub.2 -C.sub.6)alkenyl, COR.sub.5, C.sub.1 -C.sub.10 alkanoyl, CO.sub.2 R.sub.5 ', (C.sub.1 -C.sub.6 alkyl).sub.m amino, NO.sub.2, --SR.sub.5, or OR.sub.5 ;